NATURAL-KILLER-CELLS WEAKLY RESIST ENGRAFTMENT OF ALLOGENEIC, LONG-TERM, MULTILINEAGE-REPOPULATING HEMATOPOIETIC STEM-CELLS

Natural killer (NK) cells effect hybrid resistance, in which parental hematopoietic cell grafts are rejected by F-1 recipients, NK cells can also resist engraftment of fully MHC-mismatched allogeneic marrow, Ho wever, studies of NK cell-mediated alloresistance have relied on short -term proliferation, colony, or survival assays; therefore, their resu lts may not reflect effects of Mt cells on the engraftment of allogene ic pluripotent hematopoietic stem cells (PHSC), We have now addressed the role of NK cells in resisting engraftment of these most primitive hematopoietic cells, which provide long-term repopulation of multiple hematopoietic lineages, We took advantage of a nonmyeloablative condit ioning regimen that permits allogeneic marrow engraftment and inductio n of mixed chimerism in mice to evaluate the effect of host NK cell de pletion with mAb PK136 on long term competitive repopulating ability o f allogeneic marrow, Mice were pretreated with depleting anti-CD4 and anti-CD8 mAbs, then received 3 Gy of whole body irradiation and 7 Gy o f thymic irradiation prior to allogeneic bone marrow transplantation. Depending on the strain combination used, statistically significant in creases in long-term allogeneic repopulation of both myeloid and lymph oid cell lineages were observed in recipients depleted of NK cells bef ore bone marrow transplantation compared with controls, Depletion of h ost NK cells alone was sufficient to enhance donor PHSC engraftment, H owever, a statistically significant increase in allogeneic reconstitut ion in NK cell-depleted chimeras compared with control chimeras was no t observed in every experiment, and differences were most readily appa rent in a strain combination in which recipient NR cells have been sho wn to have high resistance to engraftment of donor short-term repopula ting cells, Chronic (16 weeks) anti-NK1.1 treatment resulted in higher levels of donor-type repopulation than that in animals receiving only pretransplant NK cell depletion, Our studies demonstrate for the firs t time that host NK cells resist engraftment of allogeneic longterm re populating PHSC, and provide a model for studying the elements that de termine what is regarded as ''self'' and ''non-self'' by newly develop ing NK cells.